Although multiple genes, molecular events, and cell types are implicated in systemic lupus erythematosus (SLE), apoptotic debris and its formation into immune complexes (IgG-ICs) is thought to be important in onset and/or perpetuation of disease. Our published studies show that high levels of IgG-ICs accumulate on the surface of human and murine hematopoietic cells in SLE. On murine myeloid cells, this is a consequence of diminished lysosome acidification that prevents degradation of FcgR-bound IgG-ICs. Undegraded IgG-ICs recycle to the cell surface where they accumulate and promote chronic FcgR signaling. Accumulation of undegraded IgG-ICs in the phagosome induces phagosomal membrane permeability, which allows IgG and nuclear antigens to leak into the cytosol, subsequently activating cytosolic sensors and inducing IFNa production. Using FcgRI-deficient MRL/lpr mice we found reduced accumulation of nuclear self-antigen, reduced activation of signaling effectors, reduced autoantibody production (95%), reduced BAFF levels (90%), and FcgRI-/-/MRL/lpr mice do not develop renal disease. These findings implicate lysosome defects and dysregulated FcgRI signaling as important events in SLE that lie upstream of multiple pathologies. Preliminary data show that diminished lysosome acidification is induced by events at, or upstream of, PI3k/mTOR identifying a feedforward loop between chronic PI3k activation and diminished lysosome acidification. We show that SHIP1 is integral in lysosome dysfunction, and that crosslinking FcgRI with FcgRIIb (a SHIP1 coupled receptor) on murine macrophages restores lysosome acidification and diminishes PI3k signaling. Preliminary human studies of monocytes and B cells show that lysosome dysfunction is evident in active, but not inactive, SLE. We hypothesize that lysosome dysfunction and a feedforward loop involving FcgRI/RIIa activation underlie human SLE, with the level of lysosome degradation reflecting disease activity. Thus, we propose that defects in lysosome function lead to the accumulation of surface IgG-ICs, which triggers active disease. In aims 1 and 2, cross-sectional studies will assess whether the state of lysosome function reflects disease activity, and whether the mechanisms underlying lysosome defects in human SLE are similar to those in mice. In aim 3, a longitudinal study will analyze individual SLE patients through active and inactive disease to assess whether lysosome dysfunction increases and decreases as disease relapses and remits. If successful, this study will define whether lysosome defects underlie human SLE, and whether attenuating the feedforward loop restores lysosome function in cells from patients with active disease.